TY - JOUR
T1 - Formation of inter- and intrastrand imine type DNA-DNA cross-links through secondary reactions of aldehydic adducts
AU - Sanchez, Ana M.
AU - Kozekov, Ivan D.
AU - Harris, Thomas M.
AU - Lloyd, R. Stephen
PY - 2005/11
Y1 - 2005/11
N2 - Acrolein-derived DNA adducts of guanine have previously been detected in tissues of several species, including humans, and have been shown to be mutagenic in mammalian cells and potentially carcinogenic in higher organisms. In duplex DNA, the predominant acrolein-derived lesion, γ-hydroxy-1,N 2-propanodeoxyguanosine (γ-HOPdG), exists in an equilibrated mixture of ring-opened and ring-closed forms. We have previously shown that the acyclic form can undergo secondary chemical reactions to form both interstrand DNA-DNA cross-links in a CpG sequence context and DNA-protein and DNA-peptide cross-links. Investigations using duplex DNAs containing γ-HOPdG in a CpG sequence context reversibly created at least two cross-linked species: an imine, which is a minor species but could be readily reduced by NaBH4, and a major heat labile, nonreducible species that we formulate as a carbinolamine cross-link. The DNA came to equilibrium over several days with the carbinolamine species being significantly more abundant than the reducible imine. In an effort to find other types of DNA-DNA cross-links, we have developed a high throughput screen to evaluate the effects of DNA sequence and lesion structure on the formation of reducible interstrand and intrastrand crosslinks. These data reveal that four different lesions, two involving deoxyguanosine and two involving deoxyadenosine, can react with nearby bases to form inter- and intrastrand DNA cross-links.
AB - Acrolein-derived DNA adducts of guanine have previously been detected in tissues of several species, including humans, and have been shown to be mutagenic in mammalian cells and potentially carcinogenic in higher organisms. In duplex DNA, the predominant acrolein-derived lesion, γ-hydroxy-1,N 2-propanodeoxyguanosine (γ-HOPdG), exists in an equilibrated mixture of ring-opened and ring-closed forms. We have previously shown that the acyclic form can undergo secondary chemical reactions to form both interstrand DNA-DNA cross-links in a CpG sequence context and DNA-protein and DNA-peptide cross-links. Investigations using duplex DNAs containing γ-HOPdG in a CpG sequence context reversibly created at least two cross-linked species: an imine, which is a minor species but could be readily reduced by NaBH4, and a major heat labile, nonreducible species that we formulate as a carbinolamine cross-link. The DNA came to equilibrium over several days with the carbinolamine species being significantly more abundant than the reducible imine. In an effort to find other types of DNA-DNA cross-links, we have developed a high throughput screen to evaluate the effects of DNA sequence and lesion structure on the formation of reducible interstrand and intrastrand crosslinks. These data reveal that four different lesions, two involving deoxyguanosine and two involving deoxyadenosine, can react with nearby bases to form inter- and intrastrand DNA cross-links.
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U2 - 10.1021/tx0500528
DO - 10.1021/tx0500528
M3 - Article
C2 - 16300377
AN - SCOPUS:32944468857
SN - 0893-228X
VL - 18
SP - 1683
EP - 1690
JO - Chemical Research in Toxicology
JF - Chemical Research in Toxicology
IS - 11
ER -